rs121907913

Positions:

• chr11-31802769-G-A
• chr11-31802769-G-C
• chr11-31802769-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001368894.2(PAX6):​c.76C>T​(p.Arg26Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAX6 NM_001368894.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.999

Genes affected

PAX6 (HGNC:8620): (paired box 6) This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter's anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain. [provided by RefSeq, Mar 2019]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001368894.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-31802768-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3024454.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, PAX6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-31802769-G-A is Pathogenic according to our data. Variant chr11-31802769-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 800389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX6	NM_001368894.2	c.76C>T	p.Arg26Trp	missense_variant	5/14	ENST00000640368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX6	ENST00000640368.2	c.76C>T	p.Arg26Trp	missense_variant	5/14	5	NM_001368894.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aniridia 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Aug 15, 2019

- -

Irido-corneo-trabecular dysgenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Medicine, University of Pavia

Jul 28, 2023

- -

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 31, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg26 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been observed in individuals with PAX6-related conditions (PMID: 18483559, 31700164, 34101622), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAX6 protein function. ClinVar contains an entry for this variant (Variation ID: 800389). This missense change has been observed in individual(s) with clinical features of aniridia (PMID: 27878435, 32360764). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 26 of the PAX6 protein (p.Arg26Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;.;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
Sift4G	Pathogenic	0.0	D;.;D;.;.;.;D;.;D;.;.;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
Polyphen		1.0	.;.;.;D;D;D;D;D;.;D;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.92
MutPred		0.95		Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);.;Loss of disorder (P = 0.0155);Loss of disorder (P = 0.0155);
MVP		1.0
MPC		3.3
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.97
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121907913; hg19: chr11-31824317;